Indolo[2,1-b] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith

ABSTRACT

Compounds, compositions and methods are provided for treating malaria parasites in vitro and in vivo by administering indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I.  
                 
 
     wherein A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, with the proviso that not more than three of A, B, C, D, E, F, G and H are other than carbon; wherein R 1  through R 8  are independently selected from the group consisting of, but not limited to, the halogens (F, Cl, Br, and I), alkyl groups, trifluoromethyl groups, methoxyl groups, the carboxy methyl or carboxy ethyl group (COOCH 3  or COOCH 2 CH 3 ), nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and the pharmaceutically acceptable salts thereof; and wherein X is independently selected from the group consisting of any atom especially oxygen, or any side chain necessary to make the indolo[2,1-b]quinazoline-6,12-dione compound a “prodrug” as the term is understood by one of ordinary skill in the art of medicinal chemistry. In other words, a side chain having a structure where a carbon-nitrogen double bond bears substituents that make the prodrug more water soluble and bioavailable.

FIELD OF THE INVENTION

[0001] The present invention relates to new and existingindolo[2,1-b]quinazoline-6,12-dione derivatives which are useful inkilling malaria parasites, antimalarial compositions containing thecompounds, and to methods of treating malaria with the compounds andcompositions, alone or in combination with other antimalarial agentsboth in vitro and in vivo.

BACKGROUND OF THE INVENTION

[0002] The current global situation in respect to malaria has recentlybeen detailed by Peters [W. Peters, “Drug Resistance in MalariaParasites of Animals and Man”, Advances in Parasitology, vol. 41, pp1-62 (1998)]. Currently, about two billion people are exposed to malariaand 400 million are infected with the disease. Between 100-200 millionnew cases occur each year. There are approximately 1-2 million deathsannually due to malaria. The global situation is worsening. Thepertinent facts are these: very few new antimalarial drugs have beenintroduced in the past quarter century; there is massive pressure forthe development of drug resistance due to the presence of large numbersof non-immune people in areas where malaria is efficiently transmitted;and resistance by Plasmodium falciparum and Plasmodium vivax tochloroquine is being documented in an increasingly wide geographic area.

[0003] Other frontline drugs currently used for the treatment andprevention of malaria such as mefloquine and halofantrine, are becomingincreasingly ineffective. Newly introduced artemsinin analogs(artesunate and artemether), while effective for the treatment ofmalaria, may be too toxic for long term administration required forprophylaxis. As a result, the idea of malaria eradication has beenabandoned and replaced with the more realistic target of malariacontrol.

[0004] Indolo[2,1-b]quinazoline-6,12-dione is a compound with a longhistory [see C. W. Bird, Tetrahedron, 19, 901 (1963), and referencestherein]. The structure of the compound has been verified by x-raycrystallography: M. Brufani, et al., Experientia, 27, 1249 (1971); W.Fedeli, et al., J. Chem. Soc. Perkin Transactions 2, 621 (1974). Earlydevelopments were described by Friedlander and Reschdestwensky [Ber.,48, 1843 (1915). Numerous synthetic approaches to the parent compoundhave been described: H. Karpf, et al., Tet. Let, 3007 (1978); L. A.Mitscher, et al., Heterocycles, 15, 1017 (1981); L. Capuano, et al.,Chem. Ber., 116, 741 (1983); S. Euguchi, et al., 33, 153 (1992).Indolo[2,1-b]quinazoline-6,12-dione is also a naturally occurringcompound, that is found in the higher plants such as Couroupitaguianensis Aubl [Bergman, et al., Tet. Let., 2625 (1977)]; Strobilanthescusia [G. Honda, et al., Planta Medica, 37, 172, (1979)]; Polygonumtinctorum and Isatis tinctorum [G. Honda, et al., Planta Medica, 38, 275(1980). It is produced by Candida liplytica when grown in mediacontaining an excess of tryptophan, hence its name, tryptanthrin.Indolo[2,1-b]quinzoline-6,12-dione has been shown to possessantibacterial activity against a variety of pathogenic bacteria,particularly the causative agent of tuberculosis, Mycobacteriumtuberculosis. Antibacterial activity is also claimed againstStaphylococcus aureus, Klebsiella pneumoniae, Mycobacterium smegmatis,and the fungi, Candida albicans [Mitscher, et al., “Antimicrobial Agentsfrom Higher Plants. New Synthesis and Bioactivity of Tryptanthrin(Indolo[2,1-b]quinazoline-6,12-dione) and its Analogues”, Heterocycles15, 1017-1021 (1981); Honda, G. and Tabata., M., “Isolation ofAntifungal Principal Tryptanthrin from Strobilanthes Cusia O. Kuntze,”,Planta Medica, J Med. Plant Res., 36, 85-86 (1979); Mitscher, et al.,“Part I. Antitubercular Agents from Higher Plants: Synthesis and InVitro Activity of Indolo[2,1-b]quinazoline-6,12-diones and RelatedAnalogs”, Abstracts of Papers, 35 International Congress ofAntimicrobial Agents and Chemotherapy, Abstract F 16, San Diego, Calif.,1995; Baker, W. “Part II. Antitubercular Agents from Higher Plants:Antimycobacterial Activity of Azaindoloquinazolines. Novel Agentsagainst Sensitive and Multi-drug Resistant Tuberculosis”, Abstracts ofPapers, 35 International Congress of Antimicrobial Agents andChemotherapy, Abstract F17, San Diego, Calif., 1995. To date, however,there has been no evidence or indication thatIndolo[2,1-b]quinazoline-6,12-dione and derivatives exhibitanti-malarial activity against malaria parasites or would be useful intreating malaria in vivo or in vitro.

[0005] Historically, the first antimalarial drugs stemmed from naturalremedies. The quinchona alkaloids were utilized for centuries beforetheir active principals, alkaloids such as quinine and quinidine, wereisolated and shown to be effective in themselves against malaria. Thesecompounds are devoid of useful clinical antibacterial activity. Thediscovery of the first synthetic antimalarial drugs was prompted by theselective staining of plasmodium tissues by vital stains. This lead,based upon the organic chemistry of synthetic dyes, led after a periodof perhaps twenty years, to the discovery of two classes of quinolineantimalarial drugs, the 4-aminoquinolines (such as chloroquine) and the8-aminoquinolines (such as primaquine). The biochemical basis of theantimalarial action of these agents, despite investigations spanning thelast 50 years, is still unknown. Notwithstanding their extensive use asantimalarial agents, these compounds have found no clinical utilityagainst bacterial species.

[0006] Some antibacterial agents have found application in the therapyand prevention of malaria. These include compounds whose mechanisms ofantibacterial action are well documented. Those interfering with folatemetabolism are the best known. These include the drug combinationpyrimethamine-sulfadoxine, and dapsone. However, well knownantimalarials which inhibit the metabolism of folate within theplasmodium, such as proguanil and cycloguanil, have not foundapplication as antibacterial agents despite their extensive clinicalapplication as antimalarial drugs. Doxycycline is used for malariaprophylaxis, and recently azithromycin C has shown antimalarialactivity. Many extremely powerful antibacterial agents, such as thepenicillins and cephalosporins, are devoid of antimalarial activity.

[0007] U.S. Pat. No. 5,441,955, the disclosure of which is expresslyincorporated herein by reference, describes the general Formula Idescribed herein, with the exception that it does not disclose that Xcan be a side chain necessary to make the compound of Formula I aprodrug. However, the '955 patent focuses on antibacterial compounds fortreating bacterial infections, but fails to contemplate treating malariaparasites with these compounds or using them as antimalarial agents.Thus, the inventors of this invention have discovered the unexpectedresult of these particular compounds, and the compounds with side chainsrendering the compounds prodrugs, as antimalarial agents.

[0008] That there is little relationship between antibacterial activityin a drug such as described in the '955 patent and antimalarial activityin a drug is not surprising. The bacteria and the plasmodia are verydistant genetically: Bacteria are prokaryotes and plasmodia areeukaryotes. Thus, the search for acceptable antimalarial drugs is moredifficult than the search for antibacterials as the metabolic processesof the plasmodia more closely resemble those of their eukaryotic hostswhile the genetic and metabolic gap between bacterial and mammals islarge as they belong to different kingdoms. Hence, an agent that isuseful for treating a bacterial infection is not necessarily useful fortreating a parasitic infection like malaria.

SUMMARY OF THE INVENTION

[0009] The inventors of the present invention have surprisinglydiscovered that Indolo[2,1-b]quinazoline-6,12-dione, and substitutedderivatives, exhibit potent in vitro antimalarial activity againstPlasmodium falciparum. Highly active compounds show IC₅₀ values (50%inhibitory concentration) in the 0.43 to 10 ng/mL concentration range,about one one-thousandth of the concentrations necessary to inhibitbacteria. Furthermore, these compounds are also highly active againststrains of Plasmodium falciparum which are up to 5000-fold resistant toatovoquone, 50-fold resistant to chloroquine, and 20-fold resistant tomefloquine. Therefore, this invention provides methods for inhibitingthe growth of malaria parasites in vitro and provides methods for theprevention and treatment of malaria in vivo usingindolo[2,1-b]quinazoline-6,12-dione compounds of formula I.

[0010] wherein A, B, C, D, E, F, G and H are independently selected fromcarbon and nitrogen, or A and B or C and D can be taken together to benitrogen or sulfur, with the proviso that not more than three of A, B,C, D, E, F, G and H are other than carbon; wherein R₁ through R₈ areindependently selected from the group consisting of, but not limited to,the halogens (F, Cl, Br, and I), alkyl groups, trifluoromethyl groups,methoxyl groups, the carboxy methyl or carboxy ethyl group (COOCH₃ orCOOCH₂CH₃), nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl,1-(4-alkylpiperazinyl), and the pharmaceutically acceptable saltsthereof; and wherein X is independently selected from the groupconsisting of any atom especially oxygen, or any side chain necessary tomake the indolo[2,1-b]quinazoline-6,12-dione compound a “prodrug” as theterm is understood by one of ordinary skill in the art of medicinalchemistry. In other words, a side chain having a structure where acarbon-nitrogen double bond bears substituents that make the prodrugmore water soluble and bioavailable. Improved bioavailability results ina lower effective dosage. It also makes more predictable and uniformabsorbance which increases the predictability of the response which inturn increases safety by reducing drug side effects.

[0011] An example of a prodrug containing a labile carbon-nitrogendouble bond side chain exocyclic to the tryptanthin structure is shownin Formula II. Such an example may be more water soluble, but can bereadily converted to the tryptantrin structure through hydrolysis of thecarbon-nitrogen bond to give tryptanthrin.

[0012] Another example of a labile structure attached to the ketoposition which can increase the aqueous solubility of the tryptanthrinnucleous, but will be hydrolysed back to tryptanthrin in the bloodstream is shown in Formula III.

[0013] These examples of prodrugs are not intended to limit theinvention in any way. Other side chains are contemplated that would makethe indolo[2,1-b]quinazoline-6,12-dione compound of the above formula Ia prodrug as the term is understood by one of ordinary skill in the artof medicinal chemistry. Prodrugs are described in Medicimal ChemestryPrinciples and Practice, Frank D. Cane, Royal Society of Chemistry,Cambridge England, Chapter 14, pp215-218 (1994), which is hereinincorporated by reference.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0014] In accordance with the present invention, an antimalarialcompound, composition and methods are provided for treating or controlof strains of Plasmodium falciparum, Plasmodium ovale, Plasmodiummalariae and Plasmodium vivax, either in vitro or in vivo byadministering the compound or composition of the present invention.Thus, one aspect the present invention provides a method of inhibitingthe growth of strains of P. falciparum, Plasmodium ovale, Plasmodiummalariae and P. vivax in vitro comprising contacting the strains of P.falciparum, Plasmodium ovale, Plasmodium malariae and P. vivax with agrowth inhibitory amount of a indolo[2,1-b]quinazoline-6,12-dionecompound of the formula I.

[0015] In a second aspect, the invention provides methods for inhibitingthe growth of malaria parasites in vitro and provides methods for theprevention and treatment of malaria in vivo usingindolo[2,1-b]quinazoline-6,12-dione compounds of formula I.

[0016] wherein A, B, C, D, E, F, G and H are independently selected fromcarbon and nitrogen, or A and B or C and D can be taken together to benitrogen or sulfur, with the proviso that not more than three of A, B,C, D, E, F, G and H are other than carbon; wherein R₁ through R₈ areindependently selected from the group consisting of the halogens (F, Cl,Br, and I), alkyl groups, trifluoromethyl groups, methoxyl groups, thecarboxy methyl or carboxy ethyl group (COOCH₃ or COOCH₂CH₃), nitro,aryl, heteroaryl, cyano, amino, dialkylaminoalkyl,1-(4-alkylpiperazinyl), and the pharmaceutically acceptable saltsthereof; further wherein X is independently selected from the groupconsisting of any atom especially oxygen, or any side chain necessary tomake the indolo[2,1-b]quinazoline-6,12-dione compound a “prodrug” asdescribed above and as the term is understood by one of ordinary skillin the art of medicinal chemistry.

[0017] In another aspect, the present invention proposes methods oftreating human or animal subjects suffering from a malarial infection,e.g., whether of sensitive-strain or multi-drug resistant strain(MDR-malaria) origin. Thus, the present invention provides a method oftreating a human or animal subject in need of such treatment comprisingadministering to the subject a therapeutically effective amount of aindolo[2,1-b]quinazoline-6,12-dione compound of formula (I), above,either alone or in combination with other antimalarial agents oradjuvants.

[0018] Other antimalarial agents that can be used in combination withthe compounds of the present invention include mefloquine, halofantrine,artesunate, artemether, chloroquine halofantrine, primaquine,sulfadoxine, sulfalene, pyrimethamine, doxycycline, tetracycline,azithromycin, proguanil, cycloguanil, dapsone, artemsinin, atovoquoneand the like to name a few. These compounds can be combined with thecompounds of the present invention in the same dosage, in a tablet,injectable liquid, or any other known form of administering drugs. Thesecompounds can also be administered to a patient in a separate dosage.

[0019] Other adjuvants that can be used in combination with thecompounds of the present invention are any other antiparasitic drugs.

[0020] The term “acylamino” means an acyl (CO—) radical to which anamino group is appended.

[0021] The term “loweralkyl” as used herein refers to branched orstraight chain alkyl groups comprising one to ten carbon atoms,including, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl,neopentyl and the like.

[0022] The term “alkoxy” as used herein refers to RO wherein R isloweralkyl as defined above. Representative examples of lower alkoxygroups include methoxy, ethoxy, t-butoxy and the like.

[0023] The term “alkenyl” as used herein refers to a branched orstraight chain groups comprising two to twenty carbon atoms which alsocomprises one or more carbon-carbon double bonds. Representative alkenylgroups include 2-propenyl (i.e., ally]), 3-methyl-2-butenyl,3,7-dimethyl-2,6-octadienyl, 4,8-dimethyl-3,7-nonadienyl,3,7,11-trimethyl-2,6,10-dodecatrienyl and the like.

[0024] The term “alkynyl” as used herein refers to a branched orstraight chain comprising two to twenty carbon atoms which alsocomprises one or more carbon-carbon triple bonds. Representative alkynylgroups include ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.

[0025] The term “aryl” as used herein refers to a phenyl or a C9- orC10-bicyclic carbocyclic ring system having one or more aromatic rings,including naphthyl, tetrahydronaphthyl indanyi, indenyl and the like.Aryl groups can be unsubstituted or substituted with one, two or threesubstituents independently selected from loweralkyl, haloalkyl, alkoxyand halo.

[0026] The term “arylalkyl” as used herein refers to a lower alkylradical to which is appended an aryl group. Representative arylalkylgroups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl and the like.

[0027] The term “arylalkylaryl” as used herein refers to an arylalkylgroup as previously defined appended to an aryl group. Representativearylalkylaryl groups include 4-benzylphenyl, 3-benzylphenyl,4-phenethylphenyl and the like.

[0028] The term “arylaryl” as used herein refers to an aryl group aspreviously defined which is appended to an aryl group. Representativearylaryl groups include biphenyl, 4-(1-naphthyl)phenyl,4-(2-naphthyl)phenyl and the like.

[0029] The term “aryloxy” as used herein refers to RO wherein R is anaryl group. Representative arylalkoxy groups include benzyloxy,phenylethoxy and the like.

[0030] The term “arylalkoxy” as used herein refers to a lower alkoxyradical to which is appended an aryl group. Representative arylalkoxygroup include benzyloxy, phenylethoxy and the like.

[0031] The term “aryloxyaryl” as used herein refers to an aryl radicalto which is appended an aryloxy group. Representative aryloxyaryl groupsinclude 4-phenoxypbenyl, 3-phenoxyphenyl, 4-phenoxy-1-naphthyl,3-phenoxy-1-naphthyl and the like.

[0032] The term “aryloxyarylalkyl” as used herein refers to an arylalkylradical to which is appended an aryloxy group. Representativearyloxyarylalkyl groups include 4-phenoxyphenylmethyl,3-phenoxyphenylmethyl, 4phenoxyphenylethyl, 3-phenoxyphenylethyl and thelike.

[0033] The term “arylalkoxyaryl” as used herein refers to an arylradical to which is appended an arylalkoxy group. Representativearylalkoxyaryl groups include 4-benzyloxylphenyl, 3-benzyloxyphenyl andthe like.

[0034] The term “arylalkoxyarylalkyl” as used herein refers to anarylalkyl radical to which is appended an arylalkoxy group.Representative arylalkoxyarylalkyl groups include 4-benzyloxylbenzyl,3-benzyloxybenzyl and the like.

[0035] The term “cycloalkyl” as used herein refers to an alicyclic groupcomprising from 3 to 7 carbon atoms including, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0036] The term “cycloalkylalkyl” as used herein refers to a loweralkylradical to which is appended a cycloalkyl group. Representative examplesof cycloalkylalkyl include cyclopropylmethyl, cyclohexylmethyl,2-(cyclopropyl)ethyl and the like.

[0037] The term “halogen” or “halo” as used herein refers to iodo,bromo, chloro or fluoro and the like.

[0038] The term “haloalkyl” as used herein refers to a lower alkylradical, as defined above, bearing at least one halogen substituent, forexample, chloromethyl, fluoroethyl or trifluoromethyl and the like.

[0039] The term “heterocycle” as used herein refers to an aromatic ringsystem composed of 5 or 6 atoms selected from the heteroatoms nitrogen,oxygen, and sulfur. The heterocycle may be composed of one or moreheteroatoms that are either directly connected such as pyrazole orconnected through carbon such as pyrimidine. Heterocycles can besubstituted or unsubstituted with one, two or three substituentsindependently selected from amino, alkylamino, halogen, alkyl acylamino,lower alkylaryl, alkoxy.

[0040] The term “substituted heterocycle” or “heterocyclic group” orheterocycle as used herein refers to any 3- or 2,5 4-membered ringcontaining a heteroatom selected from nitrogen, oxygen, and sulfur or a5- or 6-membered ring containing from one to three heteroatoms selectedfrom the group consisting of nitrogen, oxygen, or sulfur; wherein the5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3double bonds; wherein the nitrogen and sulfur atom maybe optionallyoxidized; wherein the nitrogen and sulfur heteroatoms maybe optionallyquarternized; and including any bicyclic group in which any of the aboveheterocyclic rings is fused to a benzene ring or another 5- or6-membered heterocyclic ring independently defined above. Heterocyclicsin which nitrogen is the heteroatom are preferred. Fully saturatedheterocyclics are also preferred.

[0041] The compounds of the invention comprise asymmetricallysubstituted carbon atoms. Such asymmetrically substituted carbon atomscan result in the compounds of the invention comprising mixtures ofstereoisomers at a particular asymmetrically substituted carbon atom ora single stereoisomer. As a result, racemic mixtures, mixtures ofdiastereomers, as well as single diastereomers or single enantiomers ofthe compounds of the invention are included in the present invention.Examples thereof are shown in Table 1, Example No. 34, 35, 71, 73 and85. The terms “S” and “R” configuration, as used herein, are as definedby the IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl Chem. (1976) 45, 13-30. The terms α and β areemployed for ring positions of cyclic compounds. The α-side of thereference plane is that side on which the preferred substituent lies atthe lowered numbered position. Those substituents lying on the oppositeside of the reference plane are assigned β descriptor. It should benoted that this usage differs from that for cyclic stereoparents, inwhich “α” means “below the plane” and denotes absolute configuration.The terms α and β configuration, as used herein, are as defined by theChemical Abstracts Index Guide-Appendix IV (1987) paragraph 203.

[0042] In yet a further aspect of the present invention, pharmaceuticalcompositions are provided which comprise a compound of the presentinvention in combination with a pharmaceutically acceptable carrier.

EXAMPLE 1 IN VITRO INHIBITION OF PLASMODIUM FALCIPARUM

[0043] The in vitro assays were conducted by using a modification of thesemiautomated microdilution technique of Desjardins et al.¹¹ and Chulayet al.¹² Two strains of Plasmodium falciparum clones, from CDC IndochinaIII (W-2), CDC Sierra Leone I (D-6). The W-2 clone is susceptible tomefloquine but resistant to chloroquine, sulfadoxine, pyrimethamine, andquinine. The D-6 clone is resistant to mefloquine but susceptible tochloroquine, sulfadoxine, pyrimethamine, and quinine. They were derivedby direct visualization and micromanipulation from patient isolates.¹³Test compounds were initially dissolved in DMSO and diluted 400-fold inRPMI 1640 culture medium supplemented with 25 mM Hepes, 32 mM HaHCO₃,and 10% Albumax I® (GIBCO BRL, Grand Island, N.Y.). These solutions weresubsequently serially diluted 2-fold with a Biomek 1000® (Beckman,Fullerton, Calif.) over 11 different concentrations. The parasites wereexposed to serial dilutions of each compound for 48 h and incubated at37° C. with 5% O₂, 5% CO₂, and 90% N₂ prior to the addition of[³H]hypoxanthine. After a further incubation of 18 h, parasite DNA washarvested from each microtiter well using Packard Filtermate 196Harvester® (Meriden, Conn.) onto glass filters. Uptake of[³H]hypoxanthine was measured with a Packard Topcount scintillationcounter. Concentration-response data were analyzed by a nonlinearregression logistic dose-response model, and the IC50 values (50%inhibitory concentrations) for each compound were calculated (see Table1, values within parentheses ( ) ). This procedure was repeated with thetest compounds initially dissolved in DMSO and diluted 400-fold in RPMI1640 culture medium supplemented with 25 mM Hepes, 32 mM HaHCO₃, andwith blood serum replacing the 10% Albumax I® (see Table 1, figureswithout parentheses). The values without parentheses indicate culture inblood serum which more closely resemble conditions in a living animal.

[0044] Four strains of Plasmodium falciparum clones, from CDC IndochinaIII (W-2), CDC Sierra Leone I (D-6), Thai WR75-TM9, and Thai TM90C2Bwere utilized in susceptibility testing and the IC₅₀ results appear inTable 1. TABLE 1 In Vitro Antimalarial Activity. Concentration ofIndolo[2,3-b]quinazoline-6,12-dione Inhibiting uptake of[³H]Hypoxanthine by Parasitized Red Blood Cells by 50% (IC₅₀, ng/mL)Example IC₅₀ IC₅₀ IC₅₀ IC₅₀ No. Structure (W-2) (D-6) (TM90C2B)(WR75-TM9) 1.

(69)* (69) 2.

(15626) (12481) 3.

(>50000) (>50000) 4.

(2.33) 15.335* (4.07) 18.888 29.846 27.319 7.165 5.

(263.86) (313.106) 6.

(502.79) (527) 7.

(512.7) (576.53) 8.

(62) (62) 9.

(403) (471) 10.

(131) (138) 11.

(2.8) 14.678 (4.9) 22.068 16.383 35.991 1.587 12.

(1.6) 5.274 5.787 6.539 (4.9) 8.535 14.239 11.005 9.738 16.914 11.11311.951 16.249 19.374 13.

(5.1) 4.335 (14.3) 14.842 10.531 9.837 21.542 13.

(5.8) 10.091 (10.0) 23.258 20.119 10.499 14.

(5.76) (10.17) 15.

(81.99) (125.58) 16.

(1014) (2160) 17.

(0.84) 2.125 (1.53) 4.928 4.207 9.932 8.002 18.

(512.93) (812.73) 19.

(1.58) 8.138 (2.57) 13.523 9.784 18.937 .485 20.

(734.34) (1054.46) 21.

(0.43) 1.278 (0.93) 0.926 2.302 2.997 1.349 22.

(262.92) (277.72) 23.

(1.67) (3.97) 24.

(0.91) 0.912 4.638 (2.01) 10.078 7.782 17.411 8.059 25.

(1990.37) (1842.69) 26.

(609.29) (589.01) 27.

(1.79) 35.649 (3.01) 95.331 41.090 139.605 5.86 28.

(126) (19.925) (124) (38.541) 29.

(130.58) (149.32) 30.

(354.29) (499.81) 31.

(134.03) (160.67) 32.

(2588.82) (3848.62) 33.

(79.58) (67.06) 34.

(601.05) (588.27) 35.

(133.86) (103.44) 36.

(4815.61) (4204.57) 37.

(3483.15) (3778.15) 38.

(203.16) (241.86) 39.

(1.88) 1.870 (3.57) 3.570 46.039 4.203 40. No entry 41.

(7.66) (12.34) 42.

(63.17) (76.43) 43.

(23,000) (38,236) 44.

(5859.64) (6924.46) 45.

(0.728) 4.741 (1.28) 6.767 8.759 1.147 14.152 46.

(6.32) 22.995 (7.61) 42.612 24.417 66.441 47. No Entry 48.

(7.74) 58.100 (13.9) 97.106 55.796 66.666 157.162 48.

(508.19) (584.37) 49.

(74.75) (73.93) 50.

(11.16) (44.22) 51.

(8760) (8693) 52.

(64.69) (73.33) 53.

(4872.21) (9006) 54.

(124.03) (74.58) 55.

(2.1) 2.303 (7.2) 11.238 5.483 14.216 56.

(117) (216) 57.

(10.58) 28.943 (20.33) 46.492 62.233 82.551 58.

(2.73) 4.272 (4.52) 10.461 8.095 17.291 59.

(2.47) 17.707 (4.37) 37.894 24.005 50.842 1.306 60.

(67.86) (78.08) 61.

(187) (247) 62.

(16) (31.27) 63.

(1.5) 1.228 (3.16) 0.946 1.162 1.965 64.

(9.25) 36.831 (15.86) 70.142 38.338 38.389 65.

(153.98) (258.88) 66.

(448.53) (516.51) 67.

(4423.91) (4435.40) 68.

(3.86) 2.455 (7.86) 4.121 3.731 5.469 69.

2.13) 8.494 (4.04) 12.333 10.170 23.876 70.

(8.69) 6.098 (13.22) 5.736 77.808 10.999 24.37 71.

(120.06) (143.32) 72.

(7465) (7860) 73.

(3.75) 2.855 (5.40) 4.889 4.464 10.506 74.

(3.52) 59.846 (2.19) 79.578 42.505 127.39 75.

(572.94) (534.47) 76.

(159.65) (223.53) 77.

(165.32) (220.3) 78.

(0.86) 0.935 (0.93) 1.966 1.764 3.297 79.

(68.76) (69.96) 80.

(6902.53) (7965.51) 81.

(73.92) (110.16) 82.

(124) (62.82) 83.

(1.8) 7.186 (3.11) 15.141 12.864 25.717 84.

(937.57) (1710.33) 85.

(105.36) (135.96) 86.

(2.3) 1.908 (3.6) 3.63 2.079 35.678 4.506 87.

(3.51) 1.252 (4.92) 2.310 0.696 4.438 88.

(177.45) (490.16) 89.

(68.77) (111.69) 90.

(3.93) 15.601 (7.59) 16.320 6.145 30.045 91.

(1.8) 5.521 4.977 (0.24) 9.064 10.137 9.825 4.594 9.941 5.438 4.4499.941 16.412

[0045] Regarding the foregoing compounds, MW refers to molecular weight,W2 refers to a malaria parasite which is susceptible to mefloquine butresistant to chloroquine, sulfadoxine, pyrimethamine and quinine. D6refers to a malaria parasite which is naturally resistant to mefloquinebut susceptible to chloroquine, sulfadoxine, pyrimethamine and quinine.The numbers associated with both W2 and D6 refer to IC₅₀ values and theunits are ng/ml.

[0046] As is shown in Table 1, the compounds 1-91 of the present areeffective in treating/reducing malaria parasites. It can be seen thatthe lower the IC₅₀ concentration, the more effective the compound. Themost effective compounds tested were compounds 21, 63, and 78.

[0047] The compounds of the invention are useful in the study of thetreatment of malaria in vitro.

[0048] Lin, A. J.; Zikry, A. B.; Kyle, D. E. J. Med. Chem., 1997, 40(9), 1399-1400, which disclosure is herein expressly incorporated byreference, describes in detail the procedures followed by the inventorsfor in vitro antimalarial studies. That disclosure also describes theprocedures for conducting in vivo antimalarial studies.

EXAMPLE 2 In Vivo Inhibition of Plasmodium falciparum, Plasmodium ovale,Plasmodium malariae and Plasmodium vivax

[0049] The in vivo efficacy of the compounds of the present inventionalone or in combination with an adjuvant can be determined in a modifiedThompson test. This test measures the survivability of mice andparasitemia clearance following administration of the compound orcomposition of the invention on days 3-5 post infection. In brief, 5×10⁵malaria parasites of one or more of the four described strains areinoculated intraperitoneally to female mice that weight approximately24-30 g. Each compound is dissolved in 5% sodium bicarbonate, and isadministered p.o. twice daily from day 3 to day 5 postinfection. Totaldosage of the compounds of the invention is 0.001 to 1000 mg/kg. Thepercent suppression of parasitemia in the treated mice compared tountreated controls is determined for each test compound. Survival ofmice to day 60 postinfection is considered a cure. Compounds areconsidered active when the survival time of the treated mice is greaterthan twice the control mice.

[0050] When the compounds of the present invention are administered withan adjuvant, the amount of adjuvant given is 0.001 to 1000 mg/kg bodyweight.

[0051] The compounds of the present invention can be used in the form ofsalts derived from inorganic or organic acids. These salts include butare not limited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, bydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylproionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate.Also, the basic nitrogen-containing groups can be quaternized with suchagents as loweralkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides, and iodides; dialkyl sulfates like dimethyl,diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides like benzyl and phenethyl bromides, and others. Water oroil-soluble or dispersible products are thereby obtained.

[0052] Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts of the compounds of Formula I includesuch inorganic acids as hydrochloric acid, sulphuric acid and phosphoricacid and such organic acids as oxalic acid, maleic acid, succinic acidand citric acid. Basic addition salts can be prepared in situ during thefinal isolation and purification of the compounds of Formula I, orseparately by reacting carboxylic acid moieties with a suitable basesuch as the hydroxide, carbonate or bicarbonate of a pharmaceuticalacceptable metal cation or with ammonia, or an organic primary,secondary or tertiary amine. Pharmaceutical acceptable salts include,but are not limited to, cations based on the alkali and alkaline earthmetals, such as sodium, lithium, potassium, calcium, magnesium, aluminumsalts and the like, as well as nontoxic ammonium, quaternary ammonium,and amine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like.

[0053] Other representative organic amines useful for the formation ofbase addition salts include diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like. The compounds of the inventionare useful in vitro in inhibiting the growth of malaria parasite, and invivo in human and animal hosts for treating malarial parasiticinfections. The compounds may be used alone or in compositions togetherwith a pharmaceutically acceptable carrier.

[0054] Total daily dose administered to a host in single or divideddoses may be in amounts, for example, from 0.001 to 1000 mg/kg bodyweight daily and more preferred from 1.0 to 50 mg/kg body weight daily.Dosage unit compositions may contain such amounts of submultiplesthereof to make up the daily dose.

[0055] The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. It willbe understood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination, and the severity of the particular diseaseundergoing therapy.

[0056] The compounds of the present invention may be administeredorally, parenterally, sublingually, by inhalation spray, rectally, ortopically in dosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration may also involve the use of transdermaladministration such as transdermal patches or ionophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques.

[0057] Injectable preparations, for example, sterile injectable aqueousor oleagenous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

[0058] Suppositories for rectal administration of the drug can beprepared by mixing the drug with a suitable nonirritating excipient suchas cocoa butter and polyethylene glycols which are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

[0059] Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium Stuart. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

[0060] Liquid dosage forms for oral administration may includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art, such aswater. Such compositions may also comprise adjuvants, such as wettingagents, emulsifying and suspending agents, and sweetening, flavoring,and perfuming agents.

[0061] The compounds of the present invention can also be administeredin the form of liposomes. As is known in the art, liposomes aregenerally derived from phospholipids or other lipid substances.Liposomes are formed by monoamellar or multiamellar hydrated liquidcrystals that are dispersed in an aqueous medium. Any nontoxic,physiologically acceptable and metabolizable lipid capable of formingliposomes can be used. The present compositions in liposome form cancontain, in addition to the compound of the present invention,stabilizers, preservatives, excipients, and the like which are wellknown in the art of formulation of drugs. The preferred lipids are thephospholipids and phosphatidyl cholines (lecithins), both natural andsynthetic. Methods to form liposomes are known in the art. See, forexample, Prescott, Ed., Methods in Cell Biology, Volume XIV, AcademicPress, New York, N.W. (1976), p.33 et seq.

[0062] While the compounds of the invention can be administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more other agents used in the treatment of malarialparasitic infections. Representative agents useful in combination withthe compounds of the invention for the treatment of malaria include, forexample, quinine, mefloquine, chloroquine, halofantrine, primaquine,sulfadoxine, sulfalene, pyrimethamine, doxycycline, tetracycline,azithromycin, proguanil, cycloguanil, dapsone, artemsinin, artesunate,artemether, atovoquone and the like.

[0063] The above compounds to be employed in combination with theindolo[2,1-b]quinazoline-6,12-dione compounds of the invention will beused in therapeutic amounts as indicated in the Physicians' DeskReference (PDR) 51st Edition (1997), which is incorporated herein byreference, or such therapeutically useful amounts as would be known toone of ordinary skill in the art such as from 0.001 to 1000 mg/kg bodyweight daily. The compounds of the invention and the other antiinfectiveagent can be administered together at the recommended maximum clinicaldosage or at lower doses. Dosage levels of the active compounds in thecompositions of the invention may be varied so as to obtain a desiredtherapeutic response depending on the route of administration, severityof the disease and the response of the patient. The combination can beadministered as separate compositions or as a single dosage formcontaining both agents. When administered as a combination, thetherapeutic agents can be formulated as separate compositions which aregiven at the same time or different times, or the therapeutic agents canbe given as a single composition.

[0064] While the preferred embodiments of the invention have beenillustrated and described, it will be appreciated that various changescan be made therein without departing from the spirit and scope of theinvention.

[0065] 1. U.S. Pat. No. 5,441,955 “Indolo[2,1-b]quinazoline-6,12-dioneAntibacterial Compounds and Methods of Use Thereof”

[0066] 2. Mitscher, et al., “Antimicrobial Agents from Higher Plants,New Synthesis and Bioactivity of Tryptanthrin(Indolo[2,1-b]quinzoline-6,12-dione) and its Analogoues”, Heterocycles15, 1017-1021 (1981)

[0067] 3. Honda, G. and Tabata., M., “Isolation of Antifingal PrincipalTryptanthrin from Strobilanthes Cusia O. Kuntze,”, Planta Medica, J Med.Plant Res., 36, 85-86 (1979).

[0068] 4. Part 1. Antitubercular Agents from Higher Plants: Synthesisand In Vitro Activity of Indolo[2,1-b]quinazoline-6,12-diones andRelated Analogs, Mitscher, L, et al., Abstracts of Papers, 35International Congress of Antimicrobial Agents and Chemotherapy,Abstract F16, San Diego, Calif., 1995.

[0069] 5. Baker, W. “Part II. Antitubercular Agents from Higher Plants:Antimycobacterial Activity of Azaindoloquinazolines. Novel Agentsagainst Sensitive and Multi-drug Resistant Tuberculosis”, Abstracts ofPapers, 35 International Congress of Antimicrobial Agents andChemotherapy, Abstract F17, San Diego, Calif., 1995.

[0070] 6. Bergman, J., et al., “The Structure of Some IndolicConstituents in Couroupita Guaianensis Aubl., Tetrahedron Letters, 30,2625-2626 (1977).

[0071] 7. Lin, A. J.; Zikry, A. B.; Kyle, D. E. J. Med. Chem., 1997, 40(9), 1399-1400.

[0072] 11. R. E. Desjardins, C. J. Canfield, D. E. Haynes, and J. D.Chulay, Quantitative Assessment of Activity In Vitro by a SemiautomatedMicrodilution Technique, Antimicrob. Agents Chemother., 16,710-718-(1979).

[0073] 12. J. D. Chulay, J. D. Haynes, and C. L. Diggs, Plasmodiumfalciparum: Assessment of In Vitro Growth by [³H]hypoxanthineIncorporation, Exp. Parasitol., 55, 138-146 (1983).

We claim:
 1. An antimalarial compound comprising one or moreindolo[2,1-b]quinazoline-6,12-dione compounds of Formula I:

wherein A, B, C, D, E, F, G and H are independently selected from carbonand nitrogen, or A and B or C and D can be taken together to be nitrogenor sulfur, with the proviso that not more than three of A, B, C, D, E,F, G and H are other than carbon; wherein R₁ through R₈ areindependently selected from the group consisting of, but not limited toF, Cl, Br, I, alkyl groups, trifluoromethyl groups, methoxyl groups, acarboxy methyl or a carboxy ethyl group (COOCH₃ or COOCH₂CH₃), nitro,aryl, heteroaryl, cyano, amino, dialkylaminoalkyl,1-(4-alkylpiperazinyl), and pharmaceutically acceptable salts thereof;and wherein X is independently selected from the group consisting ofoxygen and a side chain rendering theindolo[2,1-b]quinazoline-6,12-dione compound a prodrug.
 2. Theantimalarial compound of claim 1 , wherein theindolo[2,1-b]quinazoline-6,12-dione compound is a prodrug.
 3. Theantimalarial compound of claim 1 , wherein said compound of the FormulaI comprises asymmetrically substituted carbon atoms.
 4. The antimalarialcompound of claim 3 , wherein said asymmetrically substituted carbonatoms comprise mixtures of steroisomers.
 5. The antimalarial compound ofclaim 3 , wherein said compound comprises at least one member of thegroup consisting of racemic mixtures, diastereomer mixtures,diastereomers and single enantiomers.
 6. The antimalarial compound ofclaim 1 , wherein said indolo[2,1-b]quinazoline-6,12-dione compoundcomprises Formula II:


7. The antimalarial compound of claim 1 , wherein saidindolo[2,1-b]quinazoline-6,12-dione compound comprises Formula III


8. An antimalarial composition comprising a pharmaceutically effectiveamount of one or more indolo[2,1-b]quinazoline6,12-dione compounds ofFormula I:

wherein A, B, C, D, E, F, G and H are independently selected from carbonand nitrogen, or A and B or C and D can be taken together to be nitrogenor sulfur, with the proviso that not more than three of A, B, C, D, E,F, G and H are other than carbon; wherein R₁ through R₈ areindependently selected from the group consisting of, but not limitedtoF, Cl, Br, I, alkyl groups, trifluoromethyl groups, methoxyl groups, acarboxy methyl or a carboxy ethyl group (COOCH₃ or COOCH₂CH₃), nitro,aryl, heteroaryl, cyano, amino, dialkylaminoalkyl,1-(4-alkylpiperazinyl), and pharmaceutically acceptable salts thereof;and wherein X is independently selected from the group consisting ofoxygen and a side chain rendering theindolo[2,1-b]quinazoline-6,12-dione compound a prodrug.
 9. Theantimalarial composition of claim 8 , wherein said composition furthercomprises one or more adjuvants.
 10. The antimalarial composition ofclaim 9 , wherein said adjuvants comprise one or more antiparasiticdrug.
 11. The antimalarial composition of claim 8 , wherein saidcomposition fuirther comprises one or more antimalarial drugs selectedfrom the group consisting of mefloquine, halofantrine, artesunate,artemether, chloroquine, halofantrine, primaquine, sulfadoxine,sulfalene, pyrimethamine, doxycycline, tetracycline, azithromycine,proguanil, cycloguanil, dapsone, artemsinin and atovoquone.
 12. Theantimalarial composition of claim 8 , wherein said composition furthercomprises a pharmaceutically acceptable carrier.
 13. The antimalarialcomposition of claim 8 , wherein said composition fuirther comprises oneor more pharmaceutically acceptable additive selected from the groupconsisting of water, Ringer's solution, isotonic sodium chloridesolution, sterile fixed oils, fatty acids, cocoa butter/polyethyleneglycol, sucrose, lactose, starch, lubricating agents, buffering agentsor liposomes.
 14. The antimalarial composition of claim 8 , wherein saidsalts are selected from the group consisting of acetate, adipate,alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate,cyclopentanepropionate, dodecylsulfate, ethanesulfonate,glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, bydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pectinate,persulfate, 3-phenylproionate, picrate, pivalate, propionate, succinate,tartrate, thiocyanate, p-toluenesulfonate and undecanoate.
 15. Theantimalarial composition of claim 8 , wherein said composition is watersoluble, oil-soluble or dispersible.
 16. The antimalarial composition ofclaim 8 , wherein said composition of the Formula I is in a form of apharmaceutically acceptable acid addition salt.
 17. The antimalarialcomposition of claim 16 , wherein said acid addition salt is formed withhydrochloric acid, sulphuric acid, phosphoric acid, oxalic acid, maleicacid succinic acid or citric acid.
 18. The antimalarial composition ofclaim 8 , wherein said composition is in the form of a tablet, inhalant,parenteral injection, oral liquid, transdermal preparation, suppositoryor spray.
 19. A method of treating malaria in a host caused by malariaparasites comprising: contacting said malaria parasites in said hostwith a pharmaceutically effective, growth inhibiting amount of anantimalaria compostion comprising one or more indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I: wherein A, B, C, D,E, F, G and H are independently selected from carbon and nitrogen, or Aand B or C and D can be taken together to be nitrogen or sulfur, withthe proviso that not more than three of A, B, C, D, E, F, G and H areother than carbon; wherein R₁through R₈ are independently selected fromthe group consisting of, but not limited to F, Cl, Br, I, alkyl groups,trifluoromethyl groups, methoxyl groups, a carboxy methyl or a carboxyethyl group (COOCH₃ or COOCH₂CH₃), nitro, aryl, heteroaryl, cyano,amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and pharmaceuticallyacceptable salts thereof; and wherein X is independently selected fromthe group consisting of oxygen and a side chain rendering theindolo[2,1-b]quinazoline-6,12-dione compound a prodrug; and inhibitingthe growth of said malaria parasites.
 20. The method of claim 19 ,wherein said malaria parasites are one or more of the strains of thegroup consisting of Plasmodium falciparum, Plasmodium ovale, Plasmodiummalariae and Plasmodium vivax.
 21. The method of claim 19 , wherein saidmalaria parasites are a sensitive-strain resistant origin or amulti-drug resistant strain origin.
 22. The method of claim 19 , whereinsaid antimalarial composition further comprises an adjuvant.
 23. Themethod of claim 19 , wherein the indolo[2,1-b]quinazoline-6,12-dionecompound is a prodrug.
 24. The method of claim 23 , where said prodrugcomprises the Formula II


25. The method of claim 19 , further comprises contacting said malariaparasites with one or more additional antimalarial drugs selected fromthe group consisting of mefloquine, halofantrine, artesunate,artemether, chloroquine, halofantrine, primaquine, sulfadoxine,sulfalene, pyrimethamine, doxycycline, tetracycline, azithromycine,proguanil, cycloguanil, dapsone, artemsinin and atovoquone.
 26. Themethod of claim 25 , wherein said compound of the Formula I and saidadditional antimalarial drug contact said malaria parasites together ina single dosage form or separately in separate dosage forms givensimultaneously or at different times.
 27. The method of claim 19 ,wherein said composition of the Formula I is in the form of saltsderived from inorganic or organic acids.
 28. The method of claim 27 ,wherein said salts are selected from the group consisting of acetate,adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,cyclopentanepropionate, dodecylsulfate, ethanesulfonate,glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, bydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pectinate,persulfate, 3-phenylproionate, picrate, pivalate, propionate, succinate,tartrate, thiocyanate, p-toluenesulfonate and undecanoate.
 29. Themethod of claim 19 , wherein said composition is water soluble,oil-soluble or dispersible.
 30. The method of claim 19 , wherein saidcomposition of the Formula I is in the form of pharmaceuticallyacceptable acid addition salts.
 31. The method of claim 30 , whereinsaid acid addition salts are formed with hydrochloric acid, sulphuricacid, phosphoric acid, oxalic acid, maleic acid succinic acid or citricacid.
 32. The method of claim 19 , wherein said host is contacted withsaid composition in a daily dose of 0.001 to 1000 mg/kg of body weight.33. The method of claim 32 , wherein said host is contacted with saidcomposition in a daily dose of 1.0 to 50 mg/kg body weight.
 34. Themethod of claim 22 , wherein said host is contacted with said adjuvantin a daily dose of 0.001 to 1000 mg/kg of body weight.
 35. The method ofclaim 19 , wherein said composition is in the form of a tablet,inhalant, parenteral injection, oral liquid, transdermal preparation,suppository or spray.
 36. The method of claim 19 , wherein saidcontacting is via an administration given orally, parenterally,sublingually, rectally, topically or with an inhalation spray.
 37. Amethod of inhibiting the growth of malaria in vitro comprising:contacting said malaria parasites with a growth inhibiting amount of anantimalaria compostion comprising one or moreindolo[2,1-b]quinazoline-6,12-dione compounds of Formula I:

wherein A, B, C, D, E, F, G and H are independently selected from carbonand nitrogen, or A and B or C and D can be taken together to be nitrogenor sulfur, with the proviso that not more than three of A, B, C, D, E,F, G and H are other than carbon; wherein R₁ through R₈ areindependently selected from the group consisting of F, Cl, Br, I, alkylgroups, trifluoromethyl groups, methoxyl groups, a carboxy methyl orcarboxy ethyl group (COOCH₃ or COOCH₂CH₃), nitro, aryl, heteroaryl,cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), andpharmaceutically acceptable salts thereof; and wherein X isindependently selected from the group consisting of oxygen and a sidechain rendering the indolo[2,1-b]quinazoline-6,12-dione compound aprodrug; and inhibiting the growth of said malaria parasites.
 38. Themethod of 37, wherein said malaria parasites are present in Albuman I®serum or blood serum.
 39. The method of claim 37 , further comprisingcontacting said malaria parasites with one or more adjuvants.
 40. Themethod of claim 39 , wherein said one ore more adjuvant is selected fromthe group consisting of antiparasitic drugs.
 41. An antimalarial prodrugcomposition comprising a pharmaceutically effective amount of one ormore indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I:

wherein A, B, C, D, E, F, G and H are independently selected from carbonand nitrogen, or A and B or C and D can be taken together to be nitrogenor sulfur, with the proviso that not more than three of A, B, C, D, E,F, G and H are other than carbon; wherein R₁ through R₈ areindependently selected from the group consisting of, but not limitedtoF, Cl, Br, I, alkyl groups, trifluoromethyl groups, methoxyl groups, acarboxy methyl or a carboxy ethyl group (COOCH₃ or COOCH₂CH₃), nitro,aryl, heteroaryl, cyano, amino, dialkylaminoalkyl,1-(4-alkylpiperazinyl), and pharmaceutically acceptable salts thereof;and wherein X is a side chain rendering the indolo[2, 1-b]quinazoline-6,12-dione compound a prodrug.
 42. The antimalarialprodrug of claim 41 , comprising an indolo[2,1-b]quinazoline-6,12-dionecompounds of Formula II:


43. The antimalarial prodrug of claim 41 , comprising anindolo[2,1-b]quinazoline-6,12-dione compounds of Formula III: